Lessons from One Pandemic to Another: HIV and SARS-CoV-2 公开
Hoang, Timothy (Fall 2021)
Abstract
The latent HIV reservoir is comprised of a subset of long-lived HIV-infected CD4+ T cells that can persist during antiretroviral therapy (ART) and constitutes the main barrier to achieving HIV remission. Understanding the anatomical residence of the viral reservoir and the nature of the cells that harbor latent virus would aid in the design of therapeutics targeted at the 37.6 million people worldwide living with HIV. Using the clinically relevant non-human primate model for HIV infection and clinical specimens, we sought to investigate the poorly characterized role played by the bone-marrow (BM) compartment in HIV pathogenesis and viral persistence.
We tracked the longitudinal kinetics of BM derived CD4+ T cells before and following SIV infection and evaluated their contribution to the viral reservoir during ART. We found that BM derived memory CD4+ T cells were rapidly depleted following SIV infection, expressed high levels of PD- 1 and CTLA-4, recently proliferated (Ki-67+), and harbored SIV-DNA and SIV-RNA at levels akin to that of circulating memory CD4+ T cells. In summation, the BM compartment is a site of viral persistence that remains largely understudied and has a vital contribution to HIV viral persistence.
During late 2019 and the beginning of 2020, there was a rapid emergence and dissemination of a viral infection that caused pneumonia. This virus was then named SARS-CoV-2 and determined to be the causative agent behind the COVID-19 pandemic. Infection with SARS-CoV-2 is rapidly followed by induction of systemic inflammation, disease pathogenesis, and infiltration of immune cells into the respiratory tract. Using non-human primates, we sought to understand the underlying mechanisms driving systemic inflammation, disease pathogenesis, and evaluate the efficacy of immune modulators.
We tested baricitinib, which is a Janus Kinase (JAK) 1 and 2 inhibitor that is approved for treatment of active rheumatoid arthritis. It was reported that baricitinib could have two beneficial treatment modalities: anti-viral and anti-inflammatory properties. Viral shedding patterns in the bronchoalveolar lavage and nasal/throat swabs were not reduced with baricitinib. However, animals treated with baricitinib exhibited a profound decrease in inflammation, lung pathology, infiltration of inflammatory cells, and NETosis activity. These data support a beneficial role for using baricitinib during acute infection and elucidate the mechanism of action to mitigate disease severity.
In addition, we were interested in the role that type-I interferons (IFN-I) play following SARS-CoV- 2 infection. To understand this, we modulated IFN-I signaling using an IFN-I antagonist (IFNant) prior to infection through day 2 of infection in non-human primates. Remarkably, IFNant treatment resulted in a highly significant and consistent reduction in viral load in the lower and upper airways. Furthermore, treatment with IFNant potently reduced soluble markers of inflammation in bronchoalveolar lavage (BAL) fluid, expansion of inflammatory monocytes, and pathogenesis in the lung. Thus, IFNant treatment resulted in limited viral replication and reduction of inflammation and pathogenesis in SARS-CoV-2-infected RMs. These data indicate a vital and early role of IFN- I in regulating COVID-19 progression and emphasize the importance of identifying and understanding IFN-I pathways in COVID-19 for the development of therapeutic strategies.
These studies highlight the importance of non-human primates as models to understand infectious disease dynamics and therapeutic modalities. Taken together, these diverse studies across two different infection models underlie the importance of understanding the immune response following infection, the key determinants of pathogenesis, and how to target these pathways for therapeutic benefit.
Table of Contents
Chapter One: Introduction – HIV and SARS-CoV-2....................................................................15
Discovery and origins of HIV/AIDS .................................................................................................... 15 Viral properties and lifecycle of HIV..................................................................................................16 HIV/SIV pathogenesis and immune dysregulation ............................................................................ 17 Immune response to HIV...................................................................................................................19 Antiretroviral therapy ....................................................................................................................... 22 The viral reservoir and immune escape ............................................................................................24 Chronic infection and immune exhaustion........................................................................................27 Strategies towards HIV remission .....................................................................................................31 Non-human primate models of HIV infection ...................................................................................36 Summary for HIV...............................................................................................................................37 SARS-CoV-2 background, properties, and viral life cycle ................................................................... 37 SARS-CoV-2 clinical features .............................................................................................................40 SARS-CoV-2 Pathogenesis .................................................................................................................41 SARS-CoV-2 T Cell immunity..............................................................................................................42 SARS-CoV-2 B Cell immunity .............................................................................................................44 Deficiency to interferons can lead to severe COVID..........................................................................46 SARS-CoV-2 Therapeutics..................................................................................................................49 SARS-CoV-2 Vaccines.........................................................................................................................50 Non-human primate models of SARS-CoV-2 infection ......................................................................52
Summary for SARS-CoV-2..................................................................................................................53
Chapter Two: Bone Marrow-Derived CD4+ T Cells Are Depleted in Simian Immunodeficiency Virus-Infected Macaques and Contribute to the Size of the Replication-Competent Reservoir 54
Abstract ............................................................................................................................................55 Importance........................................................................................................................................ 55 Introduction ...................................................................................................................................... 56 Results ..............................................................................................................................................58 Discussion .........................................................................................................................................62 Materials and Methods.....................................................................................................................65 Chapter Two Figures .........................................................................................................................70
Chapter Three: Baricitinib treatment resolves lower airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques ...........................................75
Summary ........................................................................................................................................... 77 Introduction ...................................................................................................................................... 77 Results ..............................................................................................................................................79 Discussion .........................................................................................................................................90 Materials and Methods.....................................................................................................................95 Chapter Three Figures ..................................................................................................................... 115 Chapter Four: TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques..............................................................................144
Introduction .................................................................................................................................... 147 Results ............................................................................................................................................150 Discussion .......................................................................................................................................158 Materials and Methods...................................................................................................................163 Chapter Four Figures.......................................................................................................................171
Chapter Five: Modulation of type-I interferon responses results in decreased inflammation and enhanced virologic control in SARS-CoV-2-infected rhesus macaques ............................187
Summary ......................................................................................................................................... 189 Introduction .................................................................................................................................... 189 Results ............................................................................................................................................192 Discussion .......................................................................................................................................196 Materials and Methods...................................................................................................................198 Chapter Five Figures........................................................................................................................208
References .............................................................................................................................. 214
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